Methods Of Selectively Treating Asthma Using IL-13 Antagonists

• US 20170029894A1
• Filed: 04/08/2015
• Published: 02/02/2017
• Est. Priority Date: 04/11/2014
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Damask, Amy, Rotte, Michael, Lewitzky, Steven
• Granted Patent: US 10,066,267 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A47L 5/30 with driven dust-loosening tools, e.g. rotating brushes
• CPC Class Codes: A47L 9/0444 for conveying motion by endless flexible members, e.g. belts
• CPC Class Codes: A47L 9/0455 Bearing means therefor
• CPC Class Codes: A47L 9/0477 Rolls
• CPC Class Codes: A47L 9/1683 Dust collecting chambers; Dust collecting receptacles
• CPC Class Codes: A47L 9/325 for wheeled suction cleaners with steering handle
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2039/55 characterised by the host/recipient, e.g. newborn with maternal antibodies
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: C07K 16/244 Interleukins [IL]
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/51 Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 Stability, e.g. half-life, pH, temperature or enzyme-resistance
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 : Expression markers

Abstract

The disclosure is directed to novel predictive methods and personalized therapies for treating asthma. Specifically, this disclosure relates to methods of treating a patient having asthma by selectively administering an IL-13 antagonist, on the basis of that patient being genetically predisposed to have a favorable response to treatment with the IL-13 antagonist. Also disclosed herein are transmittable forms of information, diagnostic methods, and kits useful in predicting the likelihood that a patient having asthma will respond to treatment with an IL-13 antagonist.

Claims

1. A method of selectively treating a patient having asthma, comprising

i) identifying a patient having at least one AIR marker selected from the group consisting of AIR marker-1, 2, 3, 4, 5, 6, 7, 8, and 9, and

ii) thereafter administering a therapeutically effective amount of an IL-13 antagonist to the patient.

2. The method according to claim 1, wherein

said identification comprises assaying a biological sample from the patient for the presence of at least one AIR marker selected from said group.

4. The method of claim 1 further comprising determining whether said AIR marker is present in homozygous or heterozygous form wherein the presence of the at least one AIR marker in homozygous form is determinative that the patient is positive for said AIR marker.

5. The method of claim 1, wherein said AIR marker is selected from the group consisting of AIR marker 3 and AIR marker 7.

6. The method according to claim 1, further comprising the steps of:

determining whether the patient is homozygous or heterozygous for said AIR marker, and selectively administering a therapeutically effective amount of an IL-13 antagonist to the patient that is

homozygous for one of AIR marker 3 and AIR marker 7 and heterozygous at the other;

homozygous for both AIR marker 3 and AIR marker 7;

or

homozygous for AIR marker 3.

10. The method according to claim 2, wherein the step of assaying comprises assaying the biological sample for a nucleic acid product of the at least one AIR marker, or a polypeptide product of the at least one AIR marker.

11. The method according to claim 2, wherein the step of assaying comprises assaying the biological sample for a genomic sequence of the at least one AIR marker.

12. The method according to claim 2, wherein the biological sample is selected from the group consisting of blood, serum, feces, plasma, urine, tear, saliva, and a tissue sample.

13. The method according to claim 2, wherein the step of assaying comprises a technique selected from the group consisting of Northern blot analysis, polymerase chain reaction (PCR), reverse transcription-polymerase chain reaction (RT-PCR), TaqMan-based assays, direct sequencing, dynamic allele-specific hybridization, high-density oligonucleotide SNP arrays, restriction fragment length polymorphism (RFLP) assays, primer extension assays, oligonucleotide ligase assays, analysis of single strand conformation polymorphism, temperature gradient gel electrophoresis (TGGE), denaturing high performance liquid chromatography, high-resolution melting analysis, DNA mismatch-binding protein assays, SNPLex®

, capillary electrophoresis, Southern Blot, immunoassays, immunohistochemistry, ELISA, flow cytometry, Western blot, HPLC, and mass spectrometry.

15. The method according to claim 1, wherein said IL-13 antagonist competes with antibody 01951/G12 (SEQ ID NO:

14 and

     16) for binding to IL-13 under conditions that promotes said competition.

16. The method according to claim 1, wherein said IL-13 antagonist is a polypeptide or a fragment thereof, an antibody or an antigen binding fragment thereof, a Fab, an ScFv.

17. The method according to claim 1, wherein said IL-13 antagonist is an antibody or a fragment thereof that binds to an epitope of IL-13 comprising residues FCPHKV (SEQ ID NO:

67) set forth as residues 103 to 107 of SEQ ID NO;

1.

18. The method according to claim 1, wherein said IL-13 antagonist is an antibody comprising a heavy chain as set forth in SEQ ID NO:

20 and a light chain as recited in SEQ ID NO;

18.

19. The method according to claim 1, wherein said IL-13 antagonist is an antibody administered at a dose of about 50-1000 mg i.v. administered every 4 weeks.

20. The method according to claim 1, wherein the IL-13 antagonist has a K_D of about 100-200 pM,

21. The method according to claim 1, wherein the IL-13 antagonist has an in vivo half-life of about 21 days,

22. The method according to claim 1, wherein the IL-13 antagonist is an antibody selected from the group consisting of:

i. an antibody comprising one or more of the CDRs selected from the list consisting of;

(a) the V_H CDR1s shown in SEQ ID NOs;

2 or 5 (b) the V_H CDR2s shown in SEQ ID NOs;

3 or 6, (c) the V_H CDR3s shown in SEQ ID NOs;

4 or 7 (d) the V_L CDR1s shown in SEQ ID NOs;

8 or 11, (e) the V_L CDR2s shown in SEQ ID NOs;

9 or 12, (f) the V_L CDR3s shown in SEQ ID NOs;

10 or 13;

ii. an antibody comprising a heavy chain variable region CDR1 of SEQ ID NO;

2;

a heavy chain variable region CDR2 of SEQ ID NO;

3;

a heavy chain variable region CDR3 of SEQ ID NO;

4;

a light chain variable region CDR1 of SEQ ID NO;

8;

a light chain variable region CDR2 of SEQ ID NO;

9; and

a light chain variable region CDR3 of SEQ ID NO;

10;

iii. an antibody comprising a heavy chain variable region CDR1 of SEQ ID NO;

5;

a heavy chain variable region CDR2 of SEQ ID NO;

6;

a heavy chain variable region CDR3 of SEQ ID NO;

7;

a light chain variable region CDR1 of SEQ ID NO;

11;

a light chain variable region CDR2 of SEQ ID NO;

12; and

a light chain variable region CDR3 of SEQ ID NO;

13,

iv. an antibody comprising a heavy chain variable region as recited in SEQ ID NO;

14 and a light chain variable region as recited in SEQ ID NO;

16,

v. an antibody comprising a heavy chain as recited in SEQ ID NO;

20 and a light chain as recited in SEQ ID NO;

18.

3. (canceled)

7. A method of predicting the likelihood that a patient having asthma will respond to treatment with an IL-13 antagonist, comprising the step of assaying a biological sample from the patient for the presence or absence of at least one AIR marker selected from the group consisting of AIR marker-1, 2, 3, 4, 5, 6, 7, 8, and 9, wherein:

a) the presence of the at least one AIR marker is indicative of an increased likelihood that the patient will respond to treatment with the IL-13 antagonist; and

b) the absence of the at least one AIR marker is indicative of a decreased likelihood that the patient will respond to treatment with the IL-13 antagonist.

14. A method for producing a transmittable form of information for predicting the responsiveness of a patient having asthma to treatment with an IL-13 antagonist, comprising:

a) determining an increased likelihood of the patient responding to treatment with the IL-13 antagonist according to claim 7.

b) recording the result of the determining step on a tangible or intangible media form for use in transmission.

8. (canceled)

9. A method of predicting the likelihood that a patient having asthma will respond to treatment with an IL-13 antagonist, comprising the steps of:

a) assaying a biological sample from the patient for the presence or absence of at least one AIR marker, and

b) determining whether said AIR marker is present in homozygous or heterozygous form, wherein

the presence of the at least one AIR marker in homozygous form is indicative of an increased likelihood that the patient will respond to treatment with the IL-13 antagonist, wherein said at least one AIR marker is selected from the group consisting of;

i) AIR marker 3 and AIR marker 7 each present in homozygous form,

ii) AIR marker 3 present in homozygous form and AIR marker 7 in heterozygous form,

a. AIR marker 7 present in homozygous form and AIR marker 3 in heterozygous form, and

b. AIR marker 3 in homozygous form.